Early estimates of nirsevimab immunoprophylaxis effectiveness against hospital admission for respiratory syncytial virus lower respiratory tract infections in infants, Spain, October 2023 to January 2024

The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023–Jan 2024), where a universal immunisation programme began late September (coverage range: 79–99%). High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions. No protection against RSV-negative LRTI-hospitalisations was shown. These interim results could guide public-health decision-making.

The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023-Jan 2024), where a universal immunisation programme began late September (coverage range: 79-99%).High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions.No protection against RSV-negative LRTIhospitalisations was shown.These interim results could guide public-health decision-making.
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTI) in children.Nirsevimab (Beyfortus, AstraZeneca/Sanofi Pasteur), a novel monoclonal antibody against RSV, has shown promising potential in preventing paediatric RSV infections [1,2], with clinical trials showing 77.3% efficacy in preventing RSV-LRTI hospital admission in healthy infants born at term or preterm [3].Nirsevimab immunisation also showed an 83% reduction in RSVrelated hospitalisations in infants in a real-world clinical trial setting [4] and an impact on the reduction of severity of RSV-related hospitalisations [5].However, estimates of direct effectiveness have not yet been published.In late September 2023, Spain introduced the universal RSV prophylaxis into its national immunisation programme [6] for all infants born from 1 April 2023.Here, we provide the early estimates of the effectiveness of nirsevimab against hospital admission for RSV-LRTI in infants (< 9 months old) in three autonomous regions of Spain.

Active hospital surveillance of respiratory syncytial virus
We conducted a multicentre hospital-based active surveillance in nine hospitals located in three autonomous regions (five hospitals in Valencia, three in Murcia and one in Valladolid, a province of Castilla y León) in Spain.All participating hospitals routinely tested hospitalised patients for respiratory infections.The population during the data collection period consisted of all infants eligible for immunisation with nirsevimab during their first RSV season (born from 1 April 2023, n = 15,676 infants, representing 6.4% of the entire Spanish infant population eligible for immunisation).The surveillance period lasted from 1 October 2023 to between 31 December 2023 and 10 January 2024, depending on the hospital (Table 1).All infants admitted with LRTI were included.
Physician-confirmed LRTI admissions were ascertained through a retrospective review of hospital records (Murcia and Valladolid) or the database of the Valencia Hospital Network for the Study of Influenza and other respiratory viruses (VAHNSI).The VAHNSI network annually conducts a prospective active hospital-based surveillance where all infants admitted to one of the five hospitals with severe acute respiratory infection (SARI) are tested for RSV by multiplex RT-PCR [7], given parental consent.The European Centre for Disease Prevention and Control (ECDC) clinical SARI case definition [8] used in the VAHNSI project included any hospitalisation with respiratory symptoms with an onset within 14 days prior to admission.
A description of hospitalisations of infants with LRTI is shown in Table 2. Overall, 166 admissions for LRTI were included.Of the admitted infants, 95 were positive for RSV and 73 were aged 0-3 months.Murcia and Valencia reported the first RSV cases in week 40 and 41, respectively, and 75% (66/88) of cases from these regions were concentrated in weeks 47-52 2023.Valladolid had their first RSV cases in week 47 and most cases (5/7) were concentrated between weeks 48-52.All three regions still had RSV cases in week 1 2024, indicating that the season had not yet concluded.Among all 95 RSV cases, 56 (59%) had been immunised (Table 2).
Nirsevimab population-based coverage ranged between 78.7% and 98.6%, depending on the hospital (Table 1).Infants were considered immunised from the date of administration of nirsevimab (ranging from 25 September 2023 to 14 December 2023).
Immunisation status and population-based coverage data were obtained from regional vaccination registries (VIS, VACUSAN, and REVA in Valencia, Murcia, and Valladolid, respectively).The number of LRTI hospitalisations according to aetiology (RSV-positive and -negative), age (in months) and immunisation status is appended in Supplementary Figure S1.
The similarities in the methodology used to collect LRTI hospitalisations and to routinely test RSV aetiology among the three regions allowed for pooling estimates.To accomplish this, a Bayesian binomial regression, considering the hospital as a random effect to address unspecified features of each setting, was developed.

Test-negative design
Using a test-negative design (TND), data from Valencia and Murcia were pooled to estimate nirsevimab effectiveness against RSV-LRTI admissions.The immunisation odds of infants testing RSV-positive by PCR (n = 77) were compared with infants testing negative (n = 71) to estimate nirsevimab effectiveness by a Bayesian logistic regression considering hospital as a random effect.Overall nirsevimab effectiveness was 70.2% (95% CI: 38.3-88.5)(Table 3).

Sensitivity analysis
In a sensitivity analysis, we used the screening method to estimate the effectiveness of nirsevimab to prevent LRTI admissions negative for RSV, as 19.6% (95% CI: −180.8 to 82.3) and 27.5% (95% CI: −47.3 to 66.2) in Valencia and Murcia, respectively.Pooled effectiveness including both regions was 32.4% (95% CI: −27.5 to 63.4).Data from Valladolid could not be used in the sensitivity analysis because of the lack of RSV-negative cases (Table 3).

Discussion
This study provides an early estimation of the nirsevimab effectiveness in preventing RSV-LRTI hospitalisation in infants 3 months after its introduction into the Spanish national immunisation programme in a real-world setting.The strength of the study lies in the availability to pool data from hospital surveillance in three Spanish regions using a similar methodology for detecting RSV-hospitalised cases, and the simultaneous application of two independent designs (screening and TND), including a negative outcome.Our estimates indicate that nirsevimab effectiveness was greater than 70% in infants under 9 months of age who were candidates to receive the immunisation.The lack of protection in the RSV-negative hospitalisations supports the estimates.
Apart from the efficacy shown in randomised clinical trials, nirsevimab treatment was recently demonstrated to elicit an 83% reduction in RSV-related hospitalisations in infants under conditions that approximated real-world settings [4].In line with these results, our pooled estimates showed that nirsevimab was between 70% and 84% effective in preventing hospitalisations for RSV-LRTI in infants.Spain was among the first countries in Europe to introduce nirsevimab into a publicly funded national immunisation programme [6].
During the first 3 months, nirsevimab coverage in all eligible cohorts in the participating regions was around 90% on average.The active surveillance of respiratory infections performed in all nine participating hospitals allowed us to provide these estimates with two widely used methods to estimate vaccine effectiveness [9][10][11][12].These results predict a possible important impact of the nirsevimab immunisation programme on the high RSV disease burden that, according to a 2022 study from five countries in Europe, accounts for one RSVrelated hospitalisation per 56 infants in high-income settings [13].In Spain, 3.2 per 100 infants under 6 months of age are hospitalised for an RSV bronchiolitis [14].The immunisation with nirsevimab is expected to alleviate the high pressure on the healthcare systems, especially during winter periods.
The limitations of this study include considerable variation in reported effectiveness estimates because of differences in RSV circulation, hospital admission policies, sparse LRTI hospitalisations, prophylaxis coverage and case definition among hospitals and regions.However, the potential variability among hospitals was controlled for in the models.In addition, a more sensitive case definition was used in Valencia, where only severe acute respiratory infection admissions with onset of symptoms < 14 days [8] and parental consent were included, which could have led to some case loss in comparison to the other regions.Nevertheless, this issue probably did not interfere in the estimation of effectiveness.Given the short time since the implementation of the nirsevimab immunisation programme (3 months), the small number of cases prevented us from evaluating regional estimates of efficacy using TND and further evaluations later in season are warranted.

Conclusions
These early real-world data provide evidence that nirsevimab protects infants against hospitalisation for RSVassociated LRTI.While further confirmation with more studies is required, these interim results could provide valuable insights for public health decision-making.

Table 1
Nirsevimab immunisation coverage and infant hospitalisations with lower respiratory tract infections by hospital, three regions in Spain, October 2023-January 2024 (n = 166 hospitalisations) LRTI: lower respiratory tract infections; RSV: respiratory syncytial virus.a Start of data collection date was 1 October 2023.b Immunisation coverage data in Valencia are up to 12 Jan 2024, in Murcia up to 5 Jan 2024, in Valladolid up to 15 Jan 2024.c At Hospital Clínico Universitario Virgen de la Arrixaca, 11 RSV-LRTI cases were confirmed by antigen testing.The remaining cases in all hospitals were confirmed by PCR.

Table 2
Characteristics of infant hospitalisations with lower respiratory tract infections and nirsevimab immunisation status, stratified by respiratory syncytial virus (RSV) PCR results, three regions in Spain, October 2023-January 2024 (n = 166 admissions) LRTI: lower respiratory tract infections; RSV: respiratory syncytial virus.

Table 3
Effectiveness of nirsevimab against hospitalisation in infants by the screening method and test-negative design, three regions in Spain, October 2023-January 2024 (n = 166 admissions) LRTI: lower respiratory tract infection; NA: not available; OR: odds ratio; RSV: respiratory syncytial virus.a Only data from Murcia and Valencia were considered because there were no negative RSV-LRTI in Valladolid.